User:Odom:Schmidt

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Odom laboratory

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Dominic Schmidt


Dominic Schmidt, PhD

email: Dominic.Schmidt487 'at' gmail 'dot' com

Contents

Qualifications and Personal History

Education

Research

Research accomplishments

CTCF-binding locations represent regulatory sequences that are highly constrained over the course of evolution. To gain insight into how these DNA elements are conserved and spread through the genome, we defined the full spectrum of CTCF-binding sites, including a 33/34-mer motif, and identified over five thousand highly conserved, robust, and tissue-independent CTCF-binding locations by comparing ChIP-seq data from six mammals. Our data indicate that activation of retroelements has produced species-specific expansions of CTCF binding in rodents, dogs, and opossum, which often functionally serve as chromatin and transcriptional insulators. We discovered fossilized repeat elements flanking deeply conserved CTCF-binding regions, indicating that similar retrotransposon expansions occurred hundreds of millions of years ago. Repeat-driven dispersal of CTCF binding is a fundamental, ancient, and still highly active mechanism of genome evolution in mammalian lineages.:

Transcription factors (TFs) direct gene expression by binding to DNA regulatory regions. To explore the evolution of gene regulation, we experimentally determined the genome-wide occupancy of two TFs, CEBPA and HNF4A, in livers of five vertebrates. Although each TF displays highly conserved DNA binding preferences, most binding is species-specific, and aligned binding events present in all five species are rare. Regions near genes with expression levels dependent on a TF are often bound by the TF in multiple species, yet show no enhanced DNA sequence constraint. Binding divergence between species can be largely explained by sequence changes to the bound motifs. Among the binding events lost in one lineage, only half are recovered by another binding event within 10 kilobases. Our results reveal large interspecies differences in transcriptional regulation and provide insight into their evolution:

We recently showed that cohesin co-binds across the genome with transcription factors independently of CTCF, plays a functional role in estrogen-regulated transcription, and may help mediate tissue-specific transcriptional responses via long-range chromosomal interactions:


Myriad points of control influence gene expression; however, it has also been an unresolved question as to which of these mechanisms has the most influence globally. We recently showed that each layer of transcriptional regulation within the adult hepatocyte, from the binding of liver master regulators and chromatin remodelling complexes to the output of the transcriptional machinery, is directed primarily by DNA sequence. Although conservation of motifs alone cannot predict transcription factor binding, we show that within the genetic sequence there must be embedded adequate instructions to direct species-specific transcription:


We published a detailed protocol for ChIP-seq for whole tissues and cell lines. Furthermore we compared the influence of sequencing depth on peak calling using matched ChIP-chip data from the identical sequencing libraries:


I received my german diplom degree in Biochemistry at the Max Planck Institute for Molecular Genetics in the department for Vertebrate Genomics of Hans Lehrach in the laboratory of Marie-Laure Yaspo. The focus of my research was the analysis of gene regulatory networks, especially for human chromosome 21 encoded transcription factors. For this purpose I worked with ChIP-chip and developed ChIP-seq using next generation sequencing technology. We published ChIP-seq for RNA-polymerase II in human cells together with RNA-seq:

Publications

  • Schmidt D., Schwalie P.C., Wilson M.D., Ballester B., Goncalves A., Kutter C., Brown G.D, Marshall A., Flicek P., and Odom D.T. (2012). Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages. Cell,148(1-2):335-48.
  • Laudadio I., Manfroid I., Achouri Y., Schmidt D., Wilson M.D., Cordi S., Thorrez L., Knoops L., Jacquemin P., Schuit F., Pierreux C.E., Odom D.T., Peers B., Lemaigre F.P.A. (2012) Feedback Loop Between The Liver-Enriched Transcription Factor Network and Mir-122 Controls Hepatocyte Differentiation. Gastroenterology. 142, 119-29.
  • Warnatz H.J., Schmidt D., Manke T., Piccini I., Sultan M., Borodina T., Balzereit D., Wruck W., Soldatov A., Vingron M., Lehrach H., Yaspo M.L. (2011). The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in the control of the cell cycle. J Biol Chem. 286, 23521-32.
  • Ip, J.Y., Schmidt D., Pan, Q., Ramani, A.K., Fraser, A.G., Odom, D.T., and Blencowe, B. (2011). Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation. Genome Research 21, 390-401.
  • Hurtado, A., Holmes, K.A., Ross-Innes, C.S., Schmidt D., and Carroll, J.S. (2011). FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nature Genetics 43, 27-33.
  • Schmidt D., Wilson, M.D., Ballester, B., Schwalie, P.C., Brown, G.D., Marshall, A., Kutter, C., Watt, S., Martinez-Jimenez, C.P., Mackay, S., et al. (2010b). Five-vertebrate ChIP-seq reveals the evolutionary dynamics of transcription factor binding. Science 328, 1036-1040.
  • Schmidt D., Schwalie, P.C., Ross-Innes, C.S., Hurtado, A., Brown, G.D., Carroll, J.S., Flicek, P., and Odom, D.T. (2010a). A CTCF-independent role for cohesin in tissue-specific transcription. Genome Research 20, 578-588.
  • Ross-Innes, C.S., Stark, R., Holmes, K.A., Schmidt D., Spyrou, C., Russell, R., Massie, C.E., Vowler, S.L., Eldridge, M., and Carroll, J.S. (2010). Cooperative interaction between retinoic acid receptor-alpha and estrogen receptor in breast cancer. Genes & Development 24, 171-182.
  • Schmidt D., Wilson, M.D., Spyrou, C., Brown, G.D., Hadfield, J., and Odom, D.T. (2009). ChIP-seq: using high-throughput sequencing to discover protein-DNA interactions. Methods 48, 240-248.
  • Wilson, M.D., Barbosa-Morais, N.L., Schmidt D., Conboy, C.M., Vanes, L., Tybulewicz, V.L.J., Fisher, E.M.C., Tavaré, S., and Odom, D.T. (2008). Species-specific transcription in mice carrying human chromosome 21. Science 322, 434-438.
  • Schmidt D., Stark, R., Wilson, M.D., Brown, G.D., and Odom, D.T. (2008). Genome-scale validation of deep-sequencing libraries. PLoS ONE 3, e3713.
  • Sultan, M., Schulz, M.H., Richard, H., Magen, A., Klingenhoff, A., Scherf, M., Seifert, M., Borodina, T., Soldatov, A., Parkhomchuk, D., Schmidt D. et al. (2008). A global view of gene activity and alternative splicing by deep sequencing of the human transcriptome. Science 321, 956-960.

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